The extracellular assemblies of amyloid peptides in the brain play a central role in the pathology and subsequent cognitive decline in Alzheimer's disease (AD). The long-term goal of this application is to develop a novel therapeutic treatment for AD by targeting endoproteolytic cleavage reactions that lead to the formation of amyloid peptide oligomers in the brains of AD patients. Beta-secretase is the most critical protease that processes amyloid precursor protein (APP) to form pathogenic AB peptide oligomers. Thus, approaches that target specific inhibition of B secretase-mediated enzymatic cleavage in vivo may be highly beneficial for therapeutic intervention of AD. [unreadable] [unreadable] The objective of this phase I project is to determine whether cell-permeable peptides encompassing the [unreadable] IB-secretase cleavage (substrate) site in APP are capable of suppressing apoptosis in cellular models of AD disease. Many studies have convincingly demonstrated that signal sequence-based cell-permeable peptides are useful for studying and manipulating a wide range of intracellular processes, both in vitro and in vivo, including animal disease models. In Specific Aim 1, we will examine whether imported Bsecretase substrate peptides can inhibit the intracellular cleavage of APP by B secretase, leading to a reduction in AB peptide formation and aggregation in neuroblastoma cells. Westem blotting analysis will examine the inhibition of APP cleavage by these peptides. In Specific Aim 2, we will further determine whether inhibition of AIbeta peptide formation by imported substrate peptides would result in a reduction in caspase-3 activity and neurotoxicity in neuroblastoma cells, measured by a colorimetric assay and a mitochondrial staining method, respectively. The successful outcome of this study will provide a solid biologic rationale for the further study of the therapeutic potential of these agents in treating Alzheimer's disease. [unreadable] [unreadable] [unreadable]